Background: Onco-immunogenic molecule CD155 is overexpressed in various tumor microenvironments (TME) including in colorectal cancer (CRC). Tumor-associated macrophages (TAMs) are the most abundant immune cells in CRC TME and play a vital role in CRC progression and metastasis. Most studies have focused on investigating the role of CRC cell-specific CD155 on CRC progression, while the contribution of TAMs-specific CD155 is still unknown. Here, we sought to investigate the expression pattern of CD155 in CRC TAMs and its role in tumor immunity and progression. Methods: CD155 expression patterns in CRC TAMs and macrophages in paratumor or adjacent normal tissue were analyzed in 50 patients with CRC using flow cytometry and in 141 patients with CRC using immunohistochemistry. The correlation of CD155 expression level in TAMs with M1 and M2 phenotypic transition was analyzed. The role of macrophage-specific CD155 in CRC progression and tumor immune response was investigated in vitro and in vivo. We further analyzed the effect of CRC cells on the regulation of CD155 expression in macrophages. Results: CRC TAMs from clinical samples showed robustly higher expression of CD155 than macrophages from paratumor and adjacent normal tissues. The CD155 expression level was higher in TAMs of CRC at III/IV stages compared with the I/II stages and was negatively associated with the survival of patients with CRC. CD155⁺ TAMs showed an M2 phenotype and higher expression of interleukin (IL)-10 and transforming growth factor (TGF)-β. CD155⁺ macrophages promoted CRC cell migration, invasion, and tumor growth supporting the findings from the clinical tissue analysis. This effect was mainly regulated by TGF-β-induced STAT3 activation-mediated release of matrix metalloproteinases (MMP)2 and MMP9 in CRC cells. CD155^–⁄– bone marrow transplantation in wild-type mice, as well as CD155– macrophages treatment, promoted the antitumor immune response in the mice ectopic CRC model. Additionally, CRC cells released IL-4 to trigger CD155 expression in macrophages indicating the regulatory role of CRC cells in the development of CD155⁺ TAMs. Conclusions: These findings indicated that CD155⁺ TAMs are responsible for the M2-phenotype transition, immunosuppression, and tumor progression in CRC. The specific localization of CD155⁺ TAMs in CRC tissue could turn into a potential therapeutic target for CRC treatment.

An ideal tumor treatment is supposed to eliminate the primary tumor and simultaneously trigger the host antitumor immune responses to prevent tumor recurrence and metastasis. Herein, a liposome encapsulating phosphoinositide 3‐kinase gamma (PI3Kγ) inhibitor IPI‐549 and photosensitizer chlorin e6 (Ce6), denoted by LIC, is prepared for colon cancer treatment. LIC internalized into CT26 cells generates reactive oxygen species (ROS) under laser irradiation to cause immunogenic tumor cell death, during which immunostimulatory signals such as calreticulin are released to further induce T lymphocyte‐mediated tumor cell killing. Meanwhile, IPI‐549 transported by liposome can inhibit PI3Kγ in the myeloid‐derived suppressive cells (MDSCs), resulting in downregulation of arginase 1 (Arg‐1) and ROS to promote MDSCs apoptosis and reduce their immunosuppressive activity to CD8⁺ T cells. LIC‐mediated immunogenic photodynamic therapy synergizes with MDSCs‐targeting immunotherapy, which significantly inhibits tumor growth via facilitating the dendritic cell maturation and tumor infiltration of CD8⁺ T cells while decreasing the tumor infiltration of immunosuppressive regulatory T cells, MDSCs, and M2‐like tumor‐associated macrophages. Moreover, the synergistic therapy increases the number of effector memory T cells (T_EM) in spleen, which suggests a favorable immune memory to prevent tumor recurrence and metastasis. The Ce6 and IPI‐549‐coloaded multifunctional nanodrug demonstrates high efficacy in colon cancer treatment.

Background: Surgery is considered to be a potentially curative approach for gastric cancer. However, most cases are diagnosed at a very advanced stage for the lack of typical symptoms in the initial stage, which makes it difficult to completely surgical resect of tumors. Early diagnosis and precise personalized intervention are urgent issues to be solved for improving the prognosis of gastric cancer. Herein, we developed an RGD-modified ROS-responsive multifunctional nanosystem for near-infrared (NIR) imaging and photothermal therapy (PTT) against gastric cancer. Methods: Firstly, the amphiphilic polymer was synthesized by bromination reaction and nucleophilic substitution reaction of carboxymethyl chitosan (CMCh) and 4-hydroxymethyl-pinacol phenylborate (BAPE). Then, it was used to encapsulate indocyanine green (ICG) and modified with RGD to form a smart multifunctional nanoparticle targeted to gastric cancer ([email protected]). The characteristics were determined, and the targeting capacity and biosafety were evaluated both in vitro and in vivo. Furthermore, [email protected] mediated photothermal therapy (PTT) effect was studied using gastric cancer cells (SGC7901) and SGC7901 tumor model. Results: The nanoparticle exhibited suitable size (≈ 120 nm), improved aqueous stability, ROS-responsive drug release, excellent photothermal conversion efficiency, enhanced cellular uptake, and targeting capacity to tumors. Remarkably, in vivo studies suggested that [email protected] could accurately illustrate the location and margin of the SGC7901 tumor through NIR imaging in comparison with non-targeted nanoparticles. Moreover, the antitumor activity of [email protected] PTT could effectively suppress tumor growth by inducing necrosis and apoptosis in cancer cells. Additionally, [email protected] demonstrated excellent biosafety both in vitro and in vivo. Conclusion: Overall, our study provides a biocompatible theranostic nanoparticle with enhanced tumor-targeting ability and accumulation to realize NIR image-guided PTT in gastric cancer.